Is ENPP2 p.Arg585Trp (c.1753C>T) pathogenic?

ENPP2 p.Arg585Trp (c.1753C>T) is classified Uncertain significance in ENPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-16). AlphaMissense: likely benign (0.2765); Rare (popmax 0.144%, afr).

How common is ENPP2 p.Arg585Trp (c.1753C>T) in the general population?

ENPP2 p.Arg585Trp (c.1753C>T) is rare (popmax 0.144%, afr) (gnomAD).

What do computational predictors say about ENPP2 p.Arg585Trp (c.1753C>T)?

AlphaMissense predicts likely benign (score 0.2765) — an in-silico prediction, not a clinical call.

ENPP2 p.Arg585Trp

c.1753C>T · rs147145968 · VCV2351217

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2765 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.144%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2765	likely benign
REVEL	0.519	indeterminate
SaProt	LLR -3.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 81 kb · p 7.3e-06 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.144% African / African-American · 108/74,902 alleles

Filtering AF 0.122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.114%

Overall 0.0111% 179/1,613,030 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.144%	694
Remaining individualsnot grpmax-eligible	0.0144%	6,940
Admixed American	0.00833%	12,000
European (non-Finnish)	0.00449%	22,248
East Asian	0.00446%	22,434
South Asian	0.0022%	45,532

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ENPP2
Protein: p.Arg585Trp
Coding: c.1753C>T
MANE Select: NM_001040092
dbSNP: rs147145968
Type: single nucleotide variant
Location: chr8:119580143 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 91.61 · 9 PDB
Residue 585: an α-helix; a disulfide bond

Full ENPP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP2 p.Arg585Gln Uncertain significance ★ ⚠ same residue
ENPP2 p.Arg799Trp Uncertain significance ★★ ⚠ same type
ENPP2 c.973-2122T>C Benign ★★ same type
ENPP2 c.973-2129G>A Benign ★★ same type
ENPP2 p.Arg844Cys Benign/Likely benign ★★ same type
ENPP2 c.1781-1341A>C Uncertain significance ★ same type
ENPP2 c.973-1995C>A Uncertain significance ★ same type
ENPP2 c.973-1998C>T Uncertain significance ★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/enpp2-p-arg585trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown